SUMMARY This proposal explores the hypothesis that sphingolipids such as ceramides serve as common, cell-autonomous signals that impair beta cell function and contribute to the development of type 1 and type 2 diabetes. The idea is predicated upon data presented herein showing that the administration of a pharmacological inhibitor of ceramide biosynthesis to rodents preserves the beta cell and prevents the development of both forms of the disease (i.e. in Zucker Diabetic Fatty rats as well as Non-Obese Diabetic mice). The theory is further supported by studies in human and mouse islets implicating ceramides as intermediates linking saturated fatty acids and inflammatory cytokines to the impairment of insulin secretion, mitochondrial function, and beta cell survival. We will evaluate this hypothesized role for ceramides and its metabolites in the pancreatic islet through the following aims: · First, we will study new mouse models allowing for the conditional, beta cell-specific modulation of genes involved in ceramide synthesis or degradation, allowing us to determine whether the lipids are either (a) necessary or (b) sufficient for beta cell failure and the onset of frank hyperglycemia. · Second, we will test the efficacy of a new class of ceramide synthesis inhibitors targeting dihydroceramide desaturase-1 as therapeutics that improve insulin secretion and prevent type 1 or type 2 diabetes in rodents. · Third, we will determine the mechanisms through which ceramides impair the function of mouse and human islets. We will test a hypothesized role for ceramides as drivers of metabolic reprogramming using state-of-the-art metabolic tracing, mitochondrial phenotyping, and cell function assays. Findings obtained from these studies could uncover new nutrient-sensing and/or inflammatory mechanisms that modulate islet function, survival and growth. Moreover, the translational component of this work could lead to the development of new therapeutic alternatives for preventing or treating diabetes.